Duchenne muscular dystrophy in Italy: A systematic review of epidemiology, quality of life, treatment adherence, and economic impact

Objective This systematic review aims to update the evidence on Duchenne muscular dystrophy (DMD) in Italy, describing the epidemiology, quality of life (QoL) of patients and caregivers, treatment adherence, and economic impact of DMD. Methods Systematic searches were conducted in PubMed, Embase and Web of Science up to January 2023. Literature selection process, data extraction and quality assessment were performed by two independent reviewers. Study protocol was registered in PROSPERO (CRD42021245196). Results Thirteen studies were included. The prevalence of DMD in the general population is 1.7–3.4 cases per 100,000, while the birth prevalence is 21.7–28.2 per 100,000 live male births. The QoL of DMD patients and caregivers is lower than that of healthy subjects, and the burden for caregivers of DMD children is higher than that of caregivers of children with other neuromuscular disorders. The compliance of real-world DMD care to clinical guidelines recommendations in Italy is lower than in other European countries. The annual cost of illness for DMD in Italy is € 35,000–46,000 per capita while, adding intangible costs, the total cost amounts to € 70,000. Conclusion Although it is a rare disease, DMD represents a significant burden in terms of quality of life of patients and their caregivers, and economic impact.


Introduction
Duchenne muscular dystrophy (DMD) is a rare X-linked recessive neuromuscular disorder caused by mutations in the dystrophin gene that lead to absent or insufficient functional dystro-1. the prevalence and the incidence of DMD in Italy; 2. the quality of life of patients with DMD and their caregivers in Italy; 3. the adherence to the different management strategies for DMD in Italy, such as pharmacotherapy, physiotherapy and occupational therapy, and to identify factors that could facilitate or hamper the adherence; 4. the economic impact of DMD in Italy.

Literature searches
Systematic literature searches were performed in PubMed, Embase and Web of Science to retrieve studies published from January 2010 to January 2023. Only articles written in English or Italian were considered. The full search strategies are described in S2 Appendix.

Inclusion criteria
• Research question 1 (epidemiology): we included both secondary studies (systematic or narrative reviews) and primary studies (cross-sectional, cohort) describing prevalence and/or incidence of DMD in Italy; • Research question 2 (quality of life): studies of any design assessing the quality of life of DMD patients and their caregivers, both comparative (e.g. DMD vs healthy subjects) or not; • Research question 3 (adherence): studies of any design assessing the adherence to the different management strategies for DMD in Italy; • Research question 4 (economic impact): economic studies describing comparative economic evaluations (e.g. cost-effectiveness studies) or cost of illness analyses.
For all the research questions, only studies performed in Italy, or international multicenter studies with at least one Italian centre were included.

Literature screening process
The study selection process was performed independently by two review authors. Any disagreement was solved through discussion and, in the event of no agreement, a third reviewer was involved. Initially, the reviewers screened the records reading titles and abstracts, according to predefined inclusion criteria. Later, they evaluated the full-text of the potential eligible studies. The final studies included in the review have been described in the main text and in the tables, while a list of excluded studies along with the reasons for their exclusion is available as supplementary material (S3 Appendix). Bibliographic references were managed using the EndNote X7.4 software.

Data extraction
Data extraction was performed by one reviewer and verified by another reviewer using a standardized form. The following general information were extracted from the included studies: bibliographic data (first author, publication year and title), study characteristics (study design, study objective, location, study period, sample size), participant characteristics (type of disease, mean age), study outcomes (incidence/prevalence, quality of life scores, adherence measures, economic measures). In addition, for each research question we extracted the following specific information: • Research question 1 (epidemiology), secondary studies: number of included studies and their bibliographic references, epidemiological estimates (prevalence in the general population, birth prevalence, incidence). Primary studies: study population (N), epidemiological estimates.
• Research question 2 (quality of life): methods used for assessing QoL, subjects interviewed (patients and/or caregivers), presence of a reference population (e.g. healthy subjects), results.
• Research question 4 (economic impact): type of economic analysis, type of costs (direct, indirect, non-healthcare costs), discount rate, economic perspective, reference year, results.

Quality assessment of included studies
The quality assessment was performed by one reviewer and verified by another reviewer, using checklists specific to the study design of included studies. In particular, the following checklists were used: for systematic reviews, the JBI Critical Appraisal Checklist for Systematic Reviews and Research Synthesis [15]; for prevalence studies, the checklist by Hoy et al. [16]; for qualitative studies, the Critical Appraisal Skills Programme (CASP) checklist [17]; for economic studies, the Consensus Health Economic Criteria (CHEC) list [18].

Strategy for data synthesis
In our study protocol, we anticipated that a quantitative synthesis of the results through a meta-analysis would only be carried out if three or more included studies reported on the same outcome for any research question; moreover, to be combined, the studies should have to be similar in terms of PICO (patient/population, intervention, comparator, outcome). Assuming a high level of heterogeneity between the included studies, it was planned to perform random effects meta-analyses, providing cumulative estimates along with 95% confidence intervals. The heterogeneity between the included studies would have been assessed using the I 2 statistic, considering a statistical significance level of p <0.05 for all analyses. The STATA 13/SE software was indicated for the statistical analyses. It was also specified in the protocol that, in all the cases where a meta-analysis was not considered feasible, the results would have been presented narratively.

Results
The literature searches in the electronic databases identified a total of 550 records. After removing duplicates, 373 records were screened through title/abstract and 35 of these were considered eligible for full-text evaluation. Twenty-two articles were excluded after full-text screening, while 13 articles were included in the final analysis. A list of excluded studies along with reasons for exclusion is provided in S3 Appendix. Among the 13 included studies, 3 studies were used for addressing the research question 1 (epidemiology), 8 studies for the research question 2 (quality of life), 1 study for the research question 3 (adherence), and 3 studies for the research question 4 (economic impact); two studies were used to address both the research questions 2 and 4. The literature selection process is shown in the The results are presented narratively, without attempting a quantitative synthesis (metaanalysis) as the studies included in this review were heterogeneous in terms of study design, objectives and PICO.
In particular: for research question 1 (epidemiology), we found a recently published systematic review and meta-analysis that was judged to be of good quality, using the JBI Critical Appraisal Checklist for Systematic Reviews and Research Synthesis [15], and therefore we decided to present its results; for research question 2 (quality of life), the included studies differ

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in terms of study design, objectives and type of tools used to measure quality of life; for research question 3 (adherence), we included only one study; for research question 4 (economic impact) there are no comparable economic measures in all three included studies. We reported the quality assessment for each research question in the S4 Appendix.

Epidemiology
We included 3 studies: a systematic review and meta-analysis [3], a systematic review [19], and an observational prevalence study [20]. The characteristics of the two reviews are described in the Table 1 All meta-analyses showed a substantial between-study heterogeneity (�90%). Meta-regressions highlighted that the only covariate that reduced the heterogeneity of about 45% was the year in which the study began and its duration; older studies reported a higher DMD birth prevalence.
The methodological quality of the included studies was assessed through a modified version of the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist; 36/44 (82%) studies were considered of moderate quality, 8/44 (18%) studies of low quality, while no study was of high quality.
The systematic review by Theadom et al. [19] describes the prevalence of all types of muscular dystrophies and includes 38 studies in the qualitative synthesis, 22 (58%) of which reporting the DMD prevalence. The included studies reported a prevalence range in the general population of 1.0-7.7 cases per 100,000. Considering only the studies with low risk of bias, the prevalence range narrows to 1.7-4.2 / 100,000.
This review included 5 Italian studies [21,22,24,26,27] that reported a DMD prevalence range of 1.7-3.4 per 100,000; all of these studies were also included in the Crisafulli review [3].
The quality assessment showed that 15/38 studies were considered having a low risk of bias, 14/38 an unclear risk of bias, and 9/38 a high risk of bias.
The last included study was the observational study of Mostacciuolo et al. (1993) [20], that updates a previous study above described [26] by using Western blot and DNA analyses as diagnostic criteria. The epidemiological estimates concern the incidence rate in the period 1959-1968 and the prevalence rate in the year 1980, in five districts of Veneto region. The reported DMD prevalence in the general population is 3.3 per 100,000, while the birth prevalence is 26.0 per 100,000 live male births.

Quality of life
To address the research question 2 (quality of life), we identified 8 studies. The main characteristics of included studies are reported in Table 2.
The study by Baiardini et al. [28] was carried out in an Italian centre located in Genova (Liguria region) and investigated the health-related quality of life and its possible determinants in 27 Duchenne muscular dystrophy children and in their parents. The tools used were the Children Health Questionnaire (CHQ)-Parent Form 50 and the Family Strain Questionnaire (FSQ); both questionnaires were completed by caregivers. Patients scored significantly lower than reference values of healthy subjects in 10 out of 15 CHQ dimensions. The use of a wheelchair (p <0.02) and pulmonary ventilator (p <0.001) are significantly associated with a lower health-related quality of life. Conversely, FSQ scores are not affected by patient characteristics.

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Duchenne muscular dystrophy in Italy: A systematic review

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Duchenne muscular dystrophy in Italy: A systematic review The multicenter study by Cavazza et al. [29] was aimed to determine the health-related quality of life of DMD patients and their caregivers in eight European countries. The Italian participants were 87 patients and 61 caregivers who filled out the EQ-5D, Barthel Index and Zarit Burden Interview questionnaires. As for the EQ-5D, the Italian adult patients obtained an average EQ-5D VAS score lower than the average score of the other countries (45.4 vs. 50.5) while for the caregivers the EQ-5D VAS score was higher than the international mean score (78.2 vs. 74.7). The average Barthel Index of the Italian population indicates severe dependence while the Zarit Burden Interview average score shows a mild-to-moderate burden. With reference to the entire study population, the authors conclude that the HRQoL of people with DMD is much lower than that of the general population and that patients with DMD rate their health status as more harm to their physical than mental health.
Crescimanno et al. [30] conducted a study in an Italian centre located in Palermo (Sicily) involving 48 long-term ventilated adult DMD patients, aimed to assess their QoL and possible determinants. The QoL was evaluated by the Neuromuscular Quality of Life questionnaire (INQoL); in addition, four other questionnaires were administered to assess their sleep quality, psychological status and symptoms of autonomic impairment. The overall INQoL score (42.8 ± 19.2) indicates a moderately altered quality of life, mainly due to high scores in the domains related to physical health (e.g. weakness, pain) and activities of daily living; on the other hand, the psychosocial domain appears to be much less affected by the disease. Loss of independence was the most important concern (mean score: 81.1 ± 21.2). Respiratory and muscular dysfunction and subjective sleep quality were severely impaired, and significantly correlated with several aspects of QoL; symptoms of sleepiness, psychological distress or autonomic dysfunction were marginally correlated to QoL.
The multicenter study by Landfeldt et al. (2014) [31] was carried out in Germany, Italy, United Kingdom (UK), and United States (USA), with the aim to estimate the cost of illness and economic burden of DMD. The QoL was assessed through the Health Utilities Index (for patients) and the EQ -5D (for caregivers). The patients' quality of life was similar across countries and significantly lower than the reference values of the general population. In particular, the Health Utilities Index for Italian patients was 0.52 (0.45-0.58), compared to a reference value of 0.94 for healthy boys aged 15-19. As for the Italian caregivers, the EQ-5D score obtained was 0.84 (0.81-0.86). On average, the loss of caregiver quality of life compared to the general population was 0.11 points (average score for patients of all countries).
The two papers by Magliano et al. [32,33] described a cross-sectional study carried out in eight tertiary neuromuscular Italian centers from January to December 2012, that involved 502 families of patients with DMD, BMD, and LGMD. The first paper (2014) [32]  LGMD) that completed the FPQ and SNQ questionnaires; in addition to the items considered in the previous study (2014) [32], this paper describes the answers to an additional openended question that asks key relatives what they suggest to improve care-givers' quality of life.
Most of relatives (77%) reported feelings of loss, 74% stated they cried or felt depressed and 59% neglected their hobbies. The burden was higher in relatives of patients with DMD than in patients with LGMD and BMD, respectively (burden of practical activities, mean [ improvements in the quality of care, 33% suggested improvements in welfare policies, 30% recommended providing psychological support to families and patients and 19% suggested greater investment in rare disease research. In addition, regression analyses showed a higher practical and psychological burden among relatives who were unemployed, who did not live with a partner, relatives of patients with higher level of functional disabilities, who spent more daily time in caregiving, having fewer social contacts, and who perceived that they had lower levels of support for the patient's emergencies from their social network. The multicenter study by Messina et al. [34] involved 98 ambulant boys with DMD from 10 Italian centers, with the aim to assess if 12 month changes in function, assessed by 6MWT, NSAA, 10 meter timed walk/run and Gowers test, were associated to changes on HRQoL. At baseline, PedsQL items correlated with nearly all functional measures, i.e. worse functional measures corresponded to lower QoL levels. The Child Self-Report reports a significant decrease between baseline and 12 months on the PedsQL GCS (74.5 to 71.5; p = 0.04) and its first domain Physical Function Score (68.9 to 64.4; p = 0.03), corresponding to the decrease in functional outcome measures, indicating a decrease in QoL during the follow-up period. Conversely, the correlation between 12-month changes in PedsQL items and functional measures was not significant for almost all items. Similar results were obtained on the Parent Proxy-Report.
The paper of Orcesi et al. of 2014 [35] describes the development of The Strips Of Life with Emoticons Questionnaire (SOLE), a child-centred, multidimensional self-assessment tool for measuring quality of life in children with neuromuscular disorders. The questionnaire was tested in 78 children with neuromuscular disorders and 81 healthy children. Patients were recruited from 6 Italian tertiary centres, while controls (healthy children) were recruited from 4 nursery and primary schools in 2 areas of northern Italy (near Pavia and Turin). The neuromuscular disorders considered were: DMD n = 43; BMD n = 3; Duchenne-Becker muscular dystrophy n = 3; spinal muscular atrophy type II (SMA) n = 14; SMA type III n = 4; congenital myopathy n = 4; girdle dystrophy n = 3; congenital muscular dystrophy n = 1; myotonic dystrophy n = 1; myasthenia gravis n = 1; Emery-Dreifuss muscular dystrophy n = 1.
The mean total score of the SOLE questionnaire was significantly lower in children with neuromuscular disorders (141.9 ± 20.8) than in controls (163.7 ± 18.0) (p <0.001). Similar results were obtained by selecting only the DMD patients and comparing them with the males of the control group (43 DMD cases vs 44 controls): the mean total SOLE score was significantly lower in the DMD group (141.0 ± 20.5) than the control group (159.7 ± 18.2) (p <0.001).

Adherence
To address the research question 3 (adherence), we identified only the study by Landfeldt et al. of 2015 [11], aimed at comparing the experience reported by the patient (or his family) regarding the medical management of DMD in Germany, Italy, UK and USA, with the recommendations of clinical guidelines for the diagnosis and management of DMD, produced by an international, multidisciplinary group of experts [4,36]. A total of 770 patient-caregiver pairs completed the questionnaire; of these, 122 couples (16%) were Italian. The questionnaire asked questions about the patient, his health status, visits to doctors and other healthcare providers related to DMD, clinical tests and assessments, drug use, and access to medical aids and devices. The study highlighted a low adherence to the guidelines in all four countries. In particular, with reference to Italian couples, the percentage of patients undergoing visits by a general practitioner or paediatrician in the last six months was 34% (42/122) and this rate is the lowest observed (Germany 66%, UK 62%, USA 60%). Furthermore, despite the importance of routine follow-up due to the side effects associated with glucocorticoids, less than 27% (21/ 78) of Italian patients taking this class of drugs had visited a neuromuscular specialist in the last six months. Again, the Italian rate is the lowest observed among the countries (72% in Germany, 68% in UK, 62% in USA). Furthermore, it emerged that only 50% (25/50) of Italian patients with scoliosis had been visited by a physiotherapist in the last six months, compared to 80% in Germany, 55% in UK and 48% in USA. The rate of scoliosis patients visited by an orthopaedist in the last six months is also lower for Italian patients than in other countries: 18% (9/50) against 37% in Germany, 23% in UK, 29% in USA. Regarding the evaluation of lung function, also recommended every six months, the observed rate among Italian patients was 66% (37/56), compared to 81% in Germany, 61% in the UK and 62% in the USA. The observed rate among Italian ventilated patients was 46% (11/24), while it was 62% in Germany, 43% in the UK and 66% in USA. The study also reported that, despite the recommendations, the use of glucocorticoids was also highly variable among countries. In particular, Deflazacort was the most used drug in Italy (as well as in Germany and USA, whereas prednisolone was mostly prescribed in UK) according to an alternate-day dosing schedule. However, this scheme was not the most used in other countries where daily (USA) or intermittent (Germany and UK) administration prevails.
The access rate to orthotic devices and mobility aids also appeared variable: in particular, the Italian proportion was 65% for orthoses (Germany 29%, UK 65%, USA 70%) and 26% for wheelchairs; the latter is the lowest observed (Germany 55%, UK 76%, USA 58%).

Economic impact
To address the research question 4 (economic impact), we identified 3 studies (Table 3).
The study by Cavazza et al. [29] was aimed at determining the economic burden of DMD from a societal perspective, and measuring the health-related quality of life (HRQoL) of patients with DMD in Europe (see QoL paragraph). As for the Italian patients, the study reported average annual total costs per patient of € 41,547 (SD 35,811) in the year 2012; specifically, € 63,559 (SD 36,672) referring to adult patients and € 34,543 (SD 33,182) to paediatric patients. The annual direct healthcare costs per patient (e.g. drugs, exams, medical visits, etc.) amount to € 9,744 (SD 10,002), that is 23% of the total costs; in particular, € 20,601 (SD 11,230) if referring only to the adults and € 6,289 (SD 6,583) if referring only to children. Direct non-healthcare costs (e.g. professional and informal care) were much higher, being equal to 76% of the total costs (whole population: € 31,518, SD 32,408; adults: € 41,776, SD 33,691; children: € 28,258, SD 31,552). The labour productivity loss due to sick leave was on average €1,181 (SD 2,706) for adult patients, equal to approximately 2% of their total costs. The study also reports that, in all countries (except for Bulgaria), the average annual cost per patient with DMD is about ten times higher than the total per capita public health expenditure estimated by the World Health Organization.
The cross-sectional study by Landfeldt et al. of 2014 [31] estimated the total cost of illness and the economic burden of DMD from the perspective of the society and caregiver households. The study identified DMD patients through national registries in Germany, Italy, UK and USA, collecting questionnaires for a total of 770 patient-caregiver pairs; of these, 122 couples (16%) were Italian. As for Italy, the study reported an estimated total burden of illness for  [37] described an economic model for estimating the average annual cost of mortality caused by DMD in Germany, Italy, the UK and USA, according to a societal perspective. The life-years lost due to DMD in the reference year (2012) were estimated based on the incidence of the condition, which for Italy amount to 3,313 (IC 3,297-3,329) life-years, and subsequently the mortality cost was calculated using a willingness-to-pay (WTP) of € 75,000 per life-year gained. The national cost of DMD mortality in Italy was therefore estimated at € 248.5 (CI 247-250) million.

Discussion
This systematic review provides an up-to-date picture of the available evidence on DMD in Italy, focusing on four domains: epidemiology, quality of life, adherence to treatment and management strategies, and economic impact.
Three studies were identified to estimate the epidemiological burden of DMD in Italy, including a systematic review with meta-analysis, a systematic review and an observational study.
As for the prevalence in the general population, Italian studies reported a range of 1.7-3.4 cases per 100,000; this range is in line with the estimated worldwide prevalence of 2.8 per 100,000 (95% CI: 1.6-4.6) resulting from the Crisafulli meta-analysis [3]. Considering only males, the pooled global prevalence (no Italian studies) reported by Crisafulli [3] was 7.1 cases (95% CI: 5.0-10.1) per 100,000 males.
As for the birth prevalence, the Italian studies reported a range of 21.7-28.2 per 100,000 live male births; this range is slightly higher than the estimated worldwide birth prevalence of 19.8/ 100,000 live male births (95% CI: 16.6-23.6), but with overlapping confidence intervals [3].
All the included Italian studies were published between 1977 and 1999. As the dystrophin gene was discovered in 1986, prevalence studies prior to this date may have provided epidemiological estimates that may have been influenced by the lack of genetic diagnosis and

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presumably overestimated the prevalence. Therefore, more recent epidemiological studies would be needed.
Regarding the quality of life of patients with DMD and their caregivers, we identified 8 studies published between 2011 and 2019. The studies were heterogeneous in terms of study objective, design, and tools used to measure the quality of life. The only tool to measure QoL used in more than one study was the EQ-5D, used by 2 studies [29,31]. The Family Problems Questionnaire (FPQ) and the Social Network Questionnaire (SNQ) were used in the two 2 studies by Magliano [32,33], but they described different sections of the questionnaires. All other studies used different tools.
Cavazza et al. [29] reported utilities for adult patients of 0.19 (0.37) and utilities for caregivers of 0.78 (0.27); both scores are lower than those of the general population. Landfeldt et al. [31] reported utilities for DMD patients of 0.52 (0.45-0.58), compared to a reference value of 0.94 for healthy boys aged 15-19; the EQ-5D score obtained by caregivers was 0.84 (0.81-0.86) that was on average 0.11 points lower than the general population. Orcesi et al. [35] reported scores of patients with DMD significantly lower than the control population of healthy subjects using the SOLE questionnaire: 141.04 (+20.52) vs 159.69 (+18. 24).
Two studies [32,33] found a higher burden for the caregivers of DMD children compared to the caregivers of children with other neuromuscular disorders.
The most cited factors that negatively affect the quality of life of patients were motor and respiratory dysfunctions, weakness, pain, dependence in daily life activities and quality of sleep.
Among the critical issues highlighted by caregivers there were feelings of loss or sadness, social stigma and limitations in leisure activities. Despite these negative aspects, caregivers also expressed some positive aspects associated with assistance, considered as personal growth, development of a sense of resilience and altruism.
Furthermore, two studies compared the QoL of Italian patients and that of patients from other countries. One of them [29] reported that the EQ-5D VAS score of Italian adult patients (45.3) was lower than the average score of the countries participating in the study (50.5) and in particular, lower than that of Germany (62.5), UK (55.6), Spain (53.8) and Hungary (60.7), while it was higher than that of Bulgaria (39.6), France (30.0) and Sweden (28.5). On the other hand, as regards the EQ-5D VAS score of Italian caregivers (78.2), it was higher than the average of the countries (74.7) and respectively higher than that observed in all other countries, with the exception of the UK (81.5) and Sweden (80.0). The average Barthel Index of Italian patients (47.1) indicates severe dependence and was superior only to that of Spanish patients (38.9) (a lower score corresponds to a greater degree of patient dependence). Higher scores were found for Bulgaria (61.8), France (80.0), Germany (51.4) and Hungary (57.9); data for the UK and Sweden not comparable as they used a different scale. In contrast, Italian caregivers reported a subjective burden, measured by the Zarit Burden Interview, equal to 24.5, lower than that of Germany (34.7), the UK (31.3), Spain (32.5) and Sweden (37.3) but higher than the French one (14.5); data for Bulgaria and Hungary were not reported.
The second study [31] involved patients from Germany, Italy, the UK and USA. The quality of life of patients was measured using the Health Utilities Index, while that of caregivers using the EQ-5D tool. For both instruments, Italy showed slightly higher values (0 indicates death, 1 perfect health) than other countries. In Italian patients, the average utility derived from the Health Utilities Index was estimated at 0.52, compared to Germany (0.45), UK (0.43) and USA (0.45). Similarly, in Italian caregivers the EQ-5D utility estimate was 0.84, compared to Germany (0.79), UK (0.82) and USA (0.81).
Regarding adherence, the only included study [11] did not report data on adherence to a specific treatment, but rather described the compliance of real-world DMD care to clinical guidelines recommendations in four countries having different healthcare systems: Italy, Germany, UK and USA. Italian patients showed the lowest compliance compared to other countries for neuromuscular, and cardiac specialist visits, physiotherapy, and access to medical devices and aids (e.g. wheelchairs).
As for the economic impact of DMD in Italy, we found two cost of illness studies [29,31] and an economic model [37] estimating the DMD mortality costs.
However, the data collected were not directly comparable as they were expressed in different currencies. Estimates were then converted into 2021 Euros: the annual per patient direct healthcare costs ranged from € 5,142 to € 10,641 and direct non-healthcare costs from € 14,825 to € 34,419; indirect costs (productivity loss) were not comparable because in one study [29] they referred to adult patients, while in another study [31] to caregivers. The impact of the intangible costs related to QoL and the economic burden on household were estimated at € 34,681 and € 48,782 per patient/year, respectively. Landfeldt (2017) et al. [37] reported a mortality DMD cost in Italy of € 271 million, compared to € 292 million in UK, € 366 million in Germany, and € 1,319 million in USA.
In addition to the three included economic studies, we found the conference abstract by Fabriani et al. (2014) [38] aimed to estimate the average annual direct and indirect costs (currency: EUR 2012) of DMD in Italy through an economic model, that was excluded from our main analysis due to insufficient information reported. This study estimated an annual direct healthcare cost for the Italian NHS of

Strengths and limitations
This review is based on a study protocol registered in the PROSPERO database; the reporting of the review follows the PRISMA guidelines; a comprehensive literature search was performed in three large electronic databases; the literature selection process, data extraction and quality assessment were performed by two independent reviewers.
Potential limitations concern the time horizon considered for the literature search (2010-2023) and that we considered only published studies, without searching the grey literature; these limitations could have reduced the sensitivity of the search.

Conclusions
This systematic review provides an updated description of the DMD burden in Italy: however, the body of evidence on DMD from Italian data is limited. Italian epidemiological studies date back to the 80s and 90s. Regarding adherence, a study found poor compliance of Italian patients with the recommendations of clinical guidelines. As for the economic impact, two studies reported an annual cost of illness for DMD in Italy converted into 2021 Euros of € 35,000-46,000 per capita, while adding also the intangible cost related to QoL the total cost amounted to € 70,000; a study reported a mortality cost in Italy of € 271 million. The average annual cost per DMD patient was 8-10 times higher than the average Italian public health expenditure per capita. The evidence base on quality of life was wider, although highly heterogeneous, and has shown a significant burden of DMD for both patients and caregivers compared to healthy subjects and also compared to patients with other neuromuscular diseases.